Abuse of stimulants like cocaine and meth amphetamines is a significant public health problem in the United States. Although the study of traditional mammalian systems has been very informative, there are still no FDA approved therapies for their abuse. The development of new tools and models is urgently needed to address these problems. Incorporation of the fruit fly, Drosophila melanogaster, into the repertoire of models to study drug abuse has been a recent and exciting development for the field. As in mammals, dopamine is a key neurotransmitter in flies that has been found to mediate conserved behaviors to CNS stimulants that include increased locomotor activity and stereotypy. Despite the discoveries made in the fly relevant to human drug action, how stimulants elicit their behaviors in the fly at a fundamental level remain undefined. Little is knon of the neurochemistry and circuitry underlying the effects of cocaine and amphetamines in the fly aside from the fact that dopamine is a key component, and that the mushroom body is involved. In mammals, serotonin has been shown to modulate the behavioral effects of these stimulants. The underlying molecular mechanisms of this modulation at the cellular and circuitry level related to drug abuse, however, remain largely unknown. Although the overall circuitry and structure of the fly brain is different from the human brain, at a basic and fundamental level, processes involving inputs and outputs between individual neurons and larger structures and circuits and how they mechanistically communicate with each other are conserved to a significant degree between fly and mammal. A greater understanding of how these circuitries interact and communicate with each other using neurotransmitters like serotonin and dopamine to produce acute and/or adaptive changes that alter normal behavior in response to stimulants will at a fundamental level translate to a better understanding of how neurons and circuits in mammalian brain that utilize the same neurotransmitters mechanistically respond to the same drugs to produce conserved behaviors. We propose here to elucidate the neural circuitry underlying the response to methamphetamine and cocaine, and to examine the role of serotonin and serotonin receptors in these responses. For our proposed work we will combine pharmacological, genetic, behavioral, and pharmacogenetic DREADD receptor approaches to manipulate circuitry and receptor function. Significantly, our preliminary data indicate that all three serotonin receptor families in the fly (5-HT1A, 5-HT2, and 5-HT7) mediate aspects of the response to stimulant drugs. Ultimately our work may uncover new molecular and/or genetic aspects of stimulant drug abuse and facilitate the development of potential therapeutic strategies.